Deregulation of small non-coding RNAs (sncRNAs) has been associated with the onset of metastasis. We evaluated the expression of sncRNAs in patients with early-stage breast cancer, performing RNA sequencing in 60 patients for whom tumor and sentinel lymph node (SLN) samples were available, and conducting differential expression, gene ontology, enrichment and survival analyses. Sequencing annotation classified most of the sncRNAs into small nucleolar RNA (snoRNAs, 70%) and small nuclear RNA (snRNA, 13%). Our results showed no significant differences in sncRNA expression between tumor or SLNs obtained from the same patient. Differential expression analysis showed down-regulation (n = 21) sncRNAs and up-regulation (n = 2) sncRNAs in patients with locoregional metastasis. The expression of SNHG5, SNORD90, SCARNA2 and SNORD78 differentiated luminal A from luminal B tumors, whereas SNORD124 up-regulation was associated with luminal B HER2+ tumors. Discriminating analysis and receiver-operating curve analysis revealed a signature of six snoRNAs (SNORD93, SNORA16A, SNORD113-6, SNORA7A, SNORA57 and SNORA18A) that distinguished patients with locoregional metastasis and predicted patient outcome. Gene ontology and Reactome pathway analysis showed an enrichment of biological processes associated with translation initiation, protein targeting to specific cell locations, and positive regulation of Wnt and NOTCH signaling pathways, commonly involved in the promotion of metastases. Our results point to the potential of several sncRNAs as surrogate markers of lymph node metastases and patient outcome in early-stage breast cancer patients. Further preclinical and clinical studies are required to understand the biological significance of the most significant sncRNAs and to validate our results in a larger cohort of patients.

Palbociclib has shown survival benefits in hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. At present, however, no genetic predictors of palbociclib-related hematological toxicity have been validated for clinical use. The aim of this study was to evaluate whether genetic variants are associated with palbociclib toxicity and patient prognosis. Multicenter study of 113 patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer treated with palbociclib plus endocrine therapy. Genotyping of DNA from blood samples was performed to determine 18 variants in seven target genes (CYP3A4, SULT2A1, ABCB1, ABCG2, NR1I2, POR, and CDKN1B). Association analyses were performed to assess the relationship between the genetic variants and treatment-related toxicity and survival outcomes. Sixty-seven patients (59.3%) developed grade 3/4 neutropenia, 62 (54.9%) experienced disease progression, and 43 (38.1%) died. Although none of the univariate associations remained significant after Bonferroni correction, the multivariate analysis, adjusted for clinical variables, revealed several nominally significant associations. The NR1I2 gene variants rs6785049 (p = 0.01) and rs3732360 (p = 0.009) were associated with grade 3/4 neutropenia. The NR1I2 rs6785049 variant was associated with palbociclib treatment interruption (p = 0.03) and with worse progression-free (p = 0.003) and overall survival (p = 0.02). The findings of this exploratory study suggest potential associations between the NR1I2 rs6785049 variant and treatment toxicity and survival outcomes in patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer treated with palbociclib. However, these hypothesis-generating findings need to be independently validated.